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The correlation of CD19 + CD24 + CD38 + B cells and other clinicopathological variables with the proportion of circulating Tregs in breast cancer patients

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Abstract

Background

T regulatory cells (Tregs) are known to negatively control immune response. The frequency of these cells was inversely correlated with clinical outcomes of breast cancer. CD19+CD24hiCD38hi cells also play a critical role in inflammation and autoimmune disease. However, their function in tumor immune response is less studied. In this study we aimed to determine the role of CD19+CD24hiCD38hi cells and some other clinicopathological variables in increasing the proportion of Tregs in breast cancer patients.

Methods

We selected 47 patients with invasive ductal breast carcinoma and 50 healthy controls and obtained their blood samples.

Results

The proportion of circulating CD4+CD25+Foxp3+ Tregs and CD19+CD24hiCD38hi cells was significantly increased in breast cancer patients. We also found that increased proportion of Tregs in breast cancer is correlated with HER2 amplification, advanced clinical stages, serum TGF-β1 and increased CD19+CD24hiCD38hi cells in the peripheral blood.

Conclusion

Altogether, our data suggest that as much as Tregs, CD19+CD24hiCD38hi B cells could also have a part in the suppression of immune response in breast cancer.

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References

  1. Zob D, Vasilescu M, Gruia M, Anghel R. Breast cancer. Screening criteria. Chirurgia (Bucur). 2013;108(4):557–62.

    CAS  Google Scholar 

  2. Watanabe MA, Oda JM, Amarante MK, Cesar Voltarelli J. Regulatory T cells and breast cancer: implications for immunopathogenesis. Cancer Metastasis Rev. 2010;29(4):569–79. doi:10.1007/s10555-010-9247-y.

    Article  CAS  PubMed  Google Scholar 

  3. Rakha EA, Martin S, Lee AH, Morgan D, Pharoah PD, Hodi Z, Macmillan D, Ellis IO. The prognostic significance of lymphovascular invasion in invasive breast carcinoma. Cancer. 2012;118(15):3670–80. doi:10.1002/cncr.26711.

    Article  PubMed  Google Scholar 

  4. Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, Allred DC, Bartlett JM, Bilous M, Fitzgibbons P, Hanna W, Jenkins RB, Mangu PB, Paik S, Perez EA, Press MF, Spears PA, Vance GH, Viale G, Hayes DF. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol. 2013;31(31):3997–4013. doi:10.1200/JCO.2013.50.9984.

    Article  PubMed  Google Scholar 

  5. Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140(6):883–99. doi:10.1016/j.cell.2010.01.025.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Wing K, Sakaguchi S. Regulatory T cells exert checks and balances on self tolerance and autoimmunity. Nat Immunol. 2010;11(1):7–13. doi:10.1038/ni.1818.

    Article  CAS  PubMed  Google Scholar 

  7. Rech AJ, Mick R, Kaplan DE, Chang KM, Domchek SM, Vonderheide RH. Homeostasis of peripheral FoxP3(+) CD4 (+) regulatory T cells in patients with early and late stage breast cancer. Cancer Immunol Immunother. 2010;59(4):599–607. doi:10.1007/s00262-009-0780-x.

    Article  CAS  PubMed  Google Scholar 

  8. Campbell DJ, Koch MA. Phenotypical and functional specialization of FOXP3 + regulatory T cells. Nat Rev Immunol. 2011;11(2):119–30. doi:10.1038/nri2916.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Wilke CM, Wu K, Zhao E, Wang G, Zou W. Prognostic significance of regulatory T cells in tumor. Int J Cancer. 2010;127(4):748–58. doi:10.1002/ijc.25464.

    CAS  PubMed  Google Scholar 

  10. Li YQ, Liu FF, Zhang XM, Guo XJ, Ren MJ, Fu L. Tumor secretion of CCL22 activates intratumoral Treg infiltration and is independent prognostic predictor of breast cancer. PLoS One. 2013;8(10):e76379. doi:10.1371/journal.pone.0076379.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Yuan XL, Chen L, Li MX, Dong P, Xue J, Wang J, Zhang TT, Wang XA, Zhang FM, Ge HL, Shen LS, Xu D. Elevated expression of Foxp3 in tumor-infiltrating Treg cells suppresses T-cell proliferation and contributes to gastric cancer progression in a COX-2-dependent manner. Clin Immunol. 2010;134(3):277–88. doi:10.1016/j.clim.2009.10.005.

    Article  CAS  PubMed  Google Scholar 

  12. Decker T, Fischer G, Bucke W, Bucke P, Stotz F, Gruneberger A, Gropp-Meier M, Wiedemann G, Pfeiffer C, Peschel C, Gotze K. Increased number of regulatory T cells (T-regs) in the peripheral blood of patients with Her-2/neu-positive early breast cancer. J Cancer Res Clin Oncol. 2012;138(11):1945–50. doi:10.1007/s00432-012-1258-3.

    Article  CAS  PubMed  Google Scholar 

  13. Watanabe MA, Oda JM, Amarante MK, Cesar Voltarelli J. Regulatory T cells and breast cancer: implications for immunopathogenesis. Cancer Metastasis Rev. 2010;29(4):569–79. doi:10.1007/s10555-010-9247-y.

    Article  CAS  PubMed  Google Scholar 

  14. Ouyang W, Beckett O, Ma Q, Li MO. Transforming growth factor-beta signaling curbs thymic negative selection promoting regulatory T cell development. Immunity. 2010;32(5):642–53. doi:10.1016/j.immuni.2010.04.012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Gupta S, Joshi K, Wig JD, Arora SK. Intratumoral FOXP3 expression in infiltrating breast carcinoma: its association with clinicopathologic parameters and angiogenesis. Acta Oncol. 2007;46(6):792–7. doi:10.1080/02841860701233443.

    Article  CAS  PubMed  Google Scholar 

  16. Fremd C, Schuetz F, Sohn C, Beckhove P, Domschke C. B cell-regulated immune responses in tumor models and cancer patients. Oncoimmunology. 2013;2(7):e25443. doi:10.4161/onci.25443.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Wolf SD, Dittel BN, Hardardottir F, Janeway CA Jr. Experimental autoimmune encephalomyelitis induction in genetically B cell-deficient mice. J Exp Med. 1996;184(6):2271–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Blair PA, Norena LY, Flores-Borja F, Rawlings DJ, Isenberg DA, Ehrenstein MR, Mauri C. CD19(+)CD24(hi)CD38(hi) B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic Lupus Erythematosus patients. Immunity. 2010;32(1):129–40. doi:10.1016/j.immuni.2009.11.009.

    Article  CAS  PubMed  Google Scholar 

  19. Lemoine S, Morva A, Youinou P, Jamin C. Human T cells induce their own regulation through activation of B cells. J Autoimmun. 2011;36(3–4):228–38. doi:10.1016/j.jaut.2011.01.005.

    Article  CAS  PubMed  Google Scholar 

  20. Horikawa M, Minard-Colin V, Matsushita T, Tedder TF. Regulatory B cell production of IL-10 inhibits lymphoma depletion during CD20 immunotherapy in mice. J Clin Invest. 2011;121(11):4268–80. doi:10.1172/JCI59266.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Schioppa T, Moore R, Thompson RG, Rosser EC, Kulbe H, Nedospasov S, Mauri C, Coussens LM, Balkwill FR. B regulatory cells and the tumor-promoting actions of TNF-alpha during squamous carcinogenesis. Proc Natl Acad Sci USA. 2011;108(26):10662–7. doi:10.1073/pnas.1100994108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wang WW, Yuan X, Chen H, Xie G, Ma Y, Zheng Y, Zhou Y, Shen L. CD19 + CD24hiCD38hiBregs involved in downregulate helper T cells and upregulate regulatory T cells in gastric cancer. Oncotarget. 2015;6(32):33486–99.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Elston CW, Ellis IO. Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology. 1991;19(5):403–10.

    Article  CAS  PubMed  Google Scholar 

  24. Rakha EA, Reis-Filho JS, Baehner F, Dabbs DJ, Decker T, Eusebi V, Fox SB, Ichihara S, Jacquemier J, Lakhani SR, Palacios J, Richardson AL, Schnitt SJ, Schmitt FC, Tan PH, Tse GM, Badve S, Ellis IO. Breast cancer prognostic classification in the molecular era: the role of histological grade. Breast Cancer Res. 2010;12(4):207. doi:10.1186/bcr2607.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Murthy V, Chamberlain RS. Further expansion of the AJCC/UICC breast cancer staging system to encompass unique problems in the developing world. Ann Surg Oncol. 2011;18(Suppl 3):S278–80. doi:10.1245/s10434-011-1649-8.

    Article  PubMed  Google Scholar 

  26. Miyoshi H, Uchida K, Taniguchi T, Yazumi S, Matsushita M, Takaoka M, et al. Circulating naive and CD4 + CD25high regulatory T cells in patients with autoimmune pancreatitis. Pancreas. 2008;36(2):133–40.

    Article  CAS  PubMed  Google Scholar 

  27. Disis ML. Immune regulation of cancer. J Clin Oncol. 2010;28(29):4531–8. doi:10.1200/JCO.2009.27.2146.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Khoder A, Sarvaria A, Alsuliman A, Chew C, Sekine T, Cooper N, Mielke S, de Lavallade H, Muftuoglu M, Fernandez Curbelo I, Liu E, Muraro PA, Alousi A, Stringaris K, Parmar S, Shah N, Shaim H, Yvon E, Molldrem J, Rouce R, Champlin R, McNiece I, Mauri C, Shpall EJ, Rezvani K. Regulatory B cells are enriched within the IgM memory and transitional subsets in healthy donors but are deficient in chronic GVHD. Blood. 2014;124(13):2034–45. doi:10.1182/blood-2014-04-571125.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Perez SA, Karamouzis MV, Skarlos DV, Ardavanis A, Sotiriadou NN, Iliopoulou EG, Salagianni ML, Orphanos G, Baxevanis CN, Rigatos G, Papamichail M. CD4 + CD25 + regulatory T-cell frequency in HER-2/neu (HER)-positive and HER-negative advanced-stage breast cancer patients. Clin Cancer Res. 2007;13(9):2714–21. doi:10.1158/1078-0432.CCR-06-2347.

    Article  CAS  PubMed  Google Scholar 

  30. Gheybi MK, Baradaran A, Mohajeri MR, Ostovar A, Hajalikhani P, Farrokhi S. Validity of immunohistochemistry method in predicting HER-2 gene status and association of clinicopathological variables with it in invasive breast cancer patients. APMIS. 2016;124(5):365–71.

    Article  CAS  PubMed  Google Scholar 

  31. Zhu S, Lin J, Qiao G, Xu Y, Zou H. Differential regulation and function of tumor-infiltrating T cells in different stages of breast cancer patients. Tumour Biol. 2015;36(10):7907–13. doi:10.1007/s13277-015-3507-y.

    Article  CAS  PubMed  Google Scholar 

  32. Rakha EA, El-Sayed ME, Lee AH, Elston CW, Grainge MJ, Hodi Z, Blamey RW, Ellis IO. Prognostic significance of Nottingham histologic grade in invasive breast carcinoma. J Clin Oncol. 2008;26(19):3153–8. doi:10.1200/JCO.2007.15.5986.

    Article  PubMed  Google Scholar 

  33. Shevach EM, Davidson TS, Huter EN, Dipaolo RA, Andersson J. Role of TGF-Beta in the induction of Foxp3 expression and T regulatory cell function. J Clin Immunol. 2008;28(6):640–6. doi:10.1007/s10875-008-9240-1.

    Article  CAS  PubMed  Google Scholar 

  34. Balkwill F, Montfort A, Capasso M. B regulatory cells in cancer. Trends Immunol. 2013;34(4):169–73. doi:10.1016/j.it.2012.10.007.

    Article  CAS  PubMed  Google Scholar 

  35. Zhang Y, Eliav Y, Shin SU, Schreiber TH, Podack ER, Tadmor T, Rosenblatt JD. B lymphocyte inhibition of anti-tumor response depends on expansion of Treg but is independent of B-cell IL-10 secretion. Cancer Immunol Immunother. 2013;62(1):87–99. doi:10.1007/s00262-012-1313-6.

    Article  CAS  PubMed  Google Scholar 

  36. Schwartz M, Zhang Y, Rosenblatt JD. B cell regulation of the anti-tumor response and role in carcinogenesis. J Immunother Cancer. 2016;4:40.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Special thanks to Dr. Yasaman Khosravi and Mr. Pouya Iranpour for their helpful assistance.

Author information

Authors and Affiliations

  1. Persian Gulf Tropical Medicine Research Center, Bushehr University of Medical Sciences, Bushehr, Iran

    Mohammad Kazzem Gheybi

  2. Department of Immunology, Persian Gulf Tropical Medicine Research Center, Bushehr University of Medical Sciences, Bushehr, Iran

    Shokrollah Farrokhi

  3. Department of Hematology and Oncology, Bushehr University of Medical Sciences, Bushehr, Iran

    Mohammad Reza Ravanbod

  4. Department of Epidemiology, Persian Gulf Tropical Medicine Research Center, Bushehr University of Medical Sciences, Bushehr, Iran

    Afshin Ostovar

  5. Department of Hematology and Oncology, Isfahan University of Medical Sciences, Isfahan, Iran

    Valiollah Mehrzad

  6. Department of Cancer Pathology, Isfahan University of Medical Sciences, Isfahan, Iran

    Pardis Nematollahi

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  1. Mohammad Kazzem Gheybi
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Correspondence to Mohammad Kazzem Gheybi.

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Gheybi, M.K., Farrokhi, S., Ravanbod, M.R. et al. The correlation of CD19 + CD24 + CD38 + B cells and other clinicopathological variables with the proportion of circulating Tregs in breast cancer patients. Breast Cancer 24, 756–764 (2017). https://doi.org/10.1007/s12282-017-0775-y

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  • DOI: https://doi.org/10.1007/s12282-017-0775-y

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